Summary Cardiovascular disease (CVD) represents the major cause of morbidity and mortality in patients with diabetes. Despite aggressive management of levels of lipids and glucose, both types 1 and 2 diabetic patients exhibit earlier onset and more extensive atherosclerotic lesions than non-diabetic subjects, and the response to lipid- lowering strategies is significantly less robust than the beneficial effects noted in non-diabetic subjects. Preclinical studies in diabetic animals have shown accelerated progression and impaired regression of atherosclerotic plaques, as well as increased retention of macrophages (Ms) in plaques. We will focus on diabetes-driven mechanisms linked to impaired atherosclerosis regression and the specific role of M perturbation. Our proposed studies are built on the discovery that transplantation of aortic arches from Ldlr-/- mice into diabetic mice deficient in RAGE or its cytoplasmic domain binding partner, DIAPH1, required for RAGE signaling, display significantly improved plaque regression, independent of changes in plasma glucose or lipid levels, compared to wild-type diabetic mice. Our earlier studies demonstrated that activation of RAGE is a critical component of the vessel wall response to hyperglycemia and that RAGE-driven mechanisms accounted for the observed acceleration and progression of atherosclerosis. In this application, using models of hyperglycemia and insulin resistance (IR), we will test the hypothesis that the consequences of hyperglycemia and RAGE/DIAPH1-dependent mechanisms in Ms modulate M trafficking (recruitment & retentions/stasis), M inflammatory polarization and M metabolism and oxidative stress, mechanisms which converge to suppress regression of established atherosclerotic plaques in diabetes. We will test novel pharmacological antagonists of RAGE/DIAPH1 in our murine model of diabetic atherosclerosis regression. These studies will provide novel insights into diabetes specific mechanisms that promote M accumulation and impair regression, and foster the development of novel therapeutic adjuncts for diabetic atherosclerosis.